This project tests an improved dendritic cell (DC) vaccine, which is designed to promote in vivo cross presentation and determinant spreading. Based on results from our previous trials, we have made several important improvements: engineering the DC with 3 full-length, defined, tumor antigens to activate multiple CD8+ and CD4+ T cell clones (reducing the concern for antigen loss variants); providing antigen presentation for the life of the DC; providing cognate CD4+ T cell help to the CD8+ T cells (“helped” CTL); using a matured DC (a cocktail specifically matched to adenovirus (AdV) transduction signals); activating innate immunity via natural killer (NK) cell migration and activation; and boosting with systemic IFNα (for endogenous DC type 1 skewing, improved cross-priming and direct effects on T cells). Together, this vaccine strategy should more potently activate a polyclonal anti-tumor response incorporating multiple adaptive and innate effectors which we predict will lead to a higher frequency of patients who not only activate vaccine-encoded antigen-specific T cell responses, but also develop determinant spreading and a significant clinical response.

Summary

Completion of the AdVTMM2/DC +/- IFNα trial and these three aims will allow us to test novel hypotheses. We will determine: 1) Vaccine-induced clinical and immune response, correlation with subsequent induction of determinant spreading, and the impact of adding IFNα to the antigen-engineered DC vaccine; 2) Layers of potential mechanisms of response and biomarkers of immunologic and clinical response; and 3) Innate-adaptive cross-talk between DC vaccines, NK cells, vaccine-activated T cells, and systemic IFNα.

Impact

We will test a potent vaccine combination therapy which may promote a higher frequency and duration of clinical response. The examination of several predictive biomarkers (tumor infiltration and gene expression, pathogen memory, SNPs, NK cell activation) and prognostic biomarkers (adaptive cellular and humoral immunity, determinant spreading, NK cell activation, serum biomarkers, autoimmunity) may identify patients able to benefit from immune-based approaches, as well as the mechanisms of that benefit.